WO2009039944A1 - Dérivés de phénothiazine à liaison double, procédé pour les produire et leur utilisation comme médicaments - Google Patents

Dérivés de phénothiazine à liaison double, procédé pour les produire et leur utilisation comme médicaments Download PDF

Info

Publication number
WO2009039944A1
WO2009039944A1 PCT/EP2008/007219 EP2008007219W WO2009039944A1 WO 2009039944 A1 WO2009039944 A1 WO 2009039944A1 EP 2008007219 W EP2008007219 W EP 2008007219W WO 2009039944 A1 WO2009039944 A1 WO 2009039944A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
alkylene
aryl
heterocycle
inhibitors
Prior art date
Application number
PCT/EP2008/007219
Other languages
German (de)
English (en)
Inventor
Stefanie Keil
Elisabeth Defossa
Dieter Schmoll
Axel Dietrich
Johanna Kuhlmann
Karl-Christian Engel
Original Assignee
Sanofi-Aventis
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi-Aventis filed Critical Sanofi-Aventis
Priority to EP08785816A priority Critical patent/EP2203448B1/fr
Priority to AT08785816T priority patent/ATE513830T1/de
Publication of WO2009039944A1 publication Critical patent/WO2009039944A1/fr
Priority to US12/724,520 priority patent/US8207146B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Phenothiazine derivatives with double bond process for their preparation and their use as medicaments
  • the invention relates to substituted phenothiazines with double bond and their physiologically acceptable salts.
  • Penothiazine derivatives such as chlorpromazine (3- (2-chloro-4 ⁇ , 10 ⁇ -dihydro-10H-phenothiazine-10-yl) -N, iV-dimethylpropan-1-amine) are already known as neuroleptics.
  • the invention had the object of developing compounds for the treatment of diabetes.
  • these compounds are intended to lower the blood sugar level.
  • the invention therefore relates to compounds of the formula I,
  • Rl is H, (Ci-C 6) -alkyl, (C 0 -C 6) alkylene-aryl, CO- (C, -C 6) - alkyl, (C 2 -C 6) - alkylene COO- (C 0 -C 6) - alkyl, (C 2 -C 6) - alkylene-O- (C, -C6) - alkyl
  • R 2 , R 3 independently of one another are H, F, Cl, Br, CN, NO 2 , (C 0 -C 6 ) -alkylene-COO- (C 0 -C 6 ) -
  • R4, R5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , (C 0 -C 6 ) -alkylene-COO-
  • A is 5 to 10 membered heterocycle, which heterocycle may be fused to another 5 to 10 membered ring;
  • B is 4 to 8 membered cycloalkyl ring, a 4 to 10 membered heterocycle or a 6 to 10 membered aryl ring;
  • Rl is H, (Ci-C 6) -alkyl, (C 0 -C 6) alkylene-aryl, CO- (C, -C 6) - alkyl, (C 2 -C 6) alkylene-
  • R2, R3 are independently H, F Cl, Br, CN, NO 2, (C 0 -C 6) -alkylene-COO- (C 0 -C 6) - alkyl, (C 0 -C 6) - alkylene O- (C 0 -C 6) alkyl, (Ci-C6) - alkyl, (C 0 -C 6) - alkylene-CO-
  • R4, R5 independently of one another are H, F, Cl, Br, CN, SCN, NO 2 , (C 0 -C 6 ) -alkylene-COO-
  • A is 5 to 10 membered heterocycle, which heterocycle may be fused to another 5 to 10 membered ring;
  • B is 4-8 membered cycloalkyl ring
  • Rl is H, (Ci-C 6) -alkyl, (C 0 -C 6) alkylene-aryl, CO- (C, -C 6) - alkyl, (C 2 -C 6) alkylene-
  • R4 (Ci-C6) - alkyl, 0- (C 1 -C 6) - alkyl, (C 0 -C 6) - alkylene-aryl;
  • A is 5 to 10 membered heterocycle, which heterocycle may be fused to another 5 to 10 membered ring;
  • B is 4-8 membered cycloalkyl ring
  • compounds of the formula I are preferred in which R 1 is H.
  • compounds of the formula I are preferred in which R 1 is methyl.
  • compounds of formula I are preferred in which R7 is H.
  • the invention relates to compounds of formula I, in the form of their racemates, racemic mixtures and pure enantiomers as well as their diastereomers and
  • radicals or substituents can occur several times in the compounds of the formula I, they may all independently of one another have the meanings indicated and be identical or different.
  • definition (Co-C 6 ) -alkylene it is understood that either a bond or a (C 1 -C 6 ) -alkylene group may be present.
  • annealing or “annealed” is meant that another ring system is fused.
  • the further fused ring system may be aromatic or non-aromatic and carbocyclic or heterocyclic.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric and organic acids, e.g.
  • Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth salts (such as magnesium and calcium salts), trometamol salt (2-amino-2-hydroxymethyl-l, 3-propanediol), diethanolamine salt, lysine salt or ethylenediamine salt.
  • the compounds of the invention may also be in various polymorphic forms, e.g. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are a further aspect of the invention.
  • alkyl radical is meant a straight or branched hydrocarbon chain having one or more carbons, e.g. Methyl, ethyl, iso-propyl, tert-butyl, hexyl.
  • the alkyl radicals may be mono or polysubstituted by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (C -C 6! Alkyl, CONH 2, CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2, cycloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, O- (C, -C 6) -alkyl, O-CO- (C 1 -C 6) - alkyl, 0-CO- (C, C6) -aryl, 0-CO- (C, -C6) -heterocycle ,; PO 3 H 2 , SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) -alkyl, SO 2 N [(dC 6 ) -alkyl] 2 , S- (
  • alkenyl radical is meant a straight or branched hydrocarbon chain having two or more carbons and one or more double bonds, e.g. Vinyl, AHyI, pentenyl.
  • alkenyl radicals may be mono or polysubstituted by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (C, -C 6) alkyl, CONH 2, CONH (C, -C 6 ) alkyl,
  • alkynyl radical is meant a straight or branched hydrocarbon chain having two or more carbons and one or more triple bonds, e.g. Ethynyl, propynyl, hexynyl.
  • the alkynyl radicals may be mono or polysubstituted by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (C, -C 6) alkyl, CONH 2, CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2, cycloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, O- (C, - C 6) - alkyl, O-CO- (C, -C6) - alkyl, 0-CO- (C, C6) -aryl, 0-CO- (C, -C6) -heterocycle; PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (C, -C6) - alkyl, SO 2 N [(C, -C 6) alkyl] 2, S- (C, - C 6 )
  • aryl radical is understood as meaning a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralonic, indanyl or indan-1-onyl radical.
  • a cycloalkyl radical is to be understood as meaning a ring system containing one or more rings which is saturated or partially unsaturated (having one or two double bonds), which is composed exclusively of carbon atoms, for example cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
  • the cycloalkyl radicals may be mono or polysubstituted by suitable groups, for example: F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (C, -C 6) alkyl, CONH 2, CONH (C, -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2> cycloalkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, O- (C 1 -C 6 ) -alkyl, O-CO- (C r C6) alkyl, 0-CO- (C iC 6) -aryl, 0-CO- (C iC 6) -heterocycle ,;
  • NH (CH 2 ) n -aryl, SO 2 -NH (CH 2 ) n -heterocycle, SO 2 -N ((C 1 -C 6 ) -alkyl) (CH 2 ) n -aryl, SO 2 -Nt (C 1 - C 6 ) -alkyl) (CH 2 ) n -heterocycle, SO 2 -N ((CH 2 ) n -aryl) 2 , SO 2 -N ((CH 2 ) n -heterocycle) 2 where n 0 - 6 and the aryl radical or heterocyclic radical can be up to twice with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , 0- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) - Alkyl, NH 2 may be substituted; C (NH) (NH 2 ), NH 2 , NH- (C 1
  • Suitable "heterocycles” or “heterocyclic radicals” are acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H Quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, 5,6-dihydro-4H-
  • heterocycles or heterocyclic radicals may be monosubstituted or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2, CONH (C 1 -C 6) alkyl, CON [(C, -C 6) alkyl] 2, cycloalkyl, (C 2 -C 6) - alkenyl, (C 2 -C 6) - alkynyl, O- ( C, -C 6) -alkyl, 0-CO- (C, -C6) - alkyl, 0-CO- (Ci-C6) - aryl, 0-CO- (C1-C6) - heterocycle, ;
  • Compounds of the formula I activate the glucose metabolism in glucokinase-expressing cells. They are therefore well suited for the treatment and prevention of elevated blood sugar levels, obesity and the metabolic syndrome (Sagen et al., Diabetes 55, 1713-1722, Levin et al., Diabetes (2006), Sl 22-Sl 30, Matschinsky et al (2006). 55, 1-12).
  • the compounds of formula I may also be useful for the treatment or prevention of other diseases and conditions in a mammal, preferably a human, caused by increased blood sugar levels, obesity or reduced activity of glucokinase.
  • the compounds of the present invention are particularly suitable for the treatment and / or prevention of:
  • Diabetes mellitus especially type 2 diabetes, including the prevention of associated sequelae.
  • Special aspects in this context are - hyperglycemia,
  • obesity and its consequences such as dyslipidemias, atherosclerosis, coronary heart disease, cerebrovascular diseases, etc., especially those (but not limited to) characterized by one or more of the following factors: high plasma triglyceride concentrations, high postprandial plasma triglyceride concentrations, low HDL cholesterol concentration low apoA lipoprotein concentrations high LDL cholesterol concentrations small dense LDL cholesterol particles high apoB lipoprotein concentrations
  • Dyslipidemia e.g., hypertriglyceridemia and / or low HDL
  • Insulin resistance e.g., hypertriglyceridemia and / or low HDL
  • Heart failure for example, but not limited to, heart attack, hypertensive heart disease or cardiomyopathy
  • the compound (s) of the formula I can also be administered in combination with other active substances.
  • the amount of a compound of Formula I required to achieve the desired biological effect is dependent upon a number of factors, eg, the specific compound chosen, the intended use, the mode of administration, and the clinical condition of the patient.
  • the daily dose is in the range of 0.3 mg to 100 mg (typically 3 mg and 50 mg) per day per kilogram of body weight, eg 3-10 mg / kg / day.
  • an intravenous dose may range from 0.3 mg to 1.0 mg / kg, which may suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute.
  • Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 100 mg, typically from 1 ng to 100 mg per milliliter.
  • Single doses may contain, for example, from 1 mg to 10 g of the active ingredient.
  • vials for injections, and orally administrable unit dose formulations, such as tablets or capsules may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg.
  • the compounds according to formula I can themselves be used as compound, but they are preferably present with a tolerable carrier in the form of a pharmaceutical composition.
  • the carrier must of course be compatible in the sense that it is compatible with the other ingredients of the composition and is not harmful to the patient.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
  • Other pharmaceutically active substances may likewise be present, including further compounds of the formula I.
  • the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the ingredients with pharmacologically acceptable carriers and / or excipients ,
  • compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case is the nature and severity of the disease condition to be treated and on the nature of the particular compound used in accordance with formula I is dependent.
  • coated formulations and coated slow release formulations are within the scope of the invention.
  • Suitable pharmaceutical compounds for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each containing a certain amount of the compound of formula I; as a powder or granules; as a solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • these compositions may be prepared by any suitable pharmaceutical method comprising a step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients).
  • the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded, if necessary.
  • a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients.
  • Compressed tablets can be prepared by tableting the compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant in a suitable machine.
  • Molded tablets may be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • compositions suitable for peroral (sublingual) administration include lozenges containing a compound of formula I with a flavor, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
  • Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula I which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as an injection. These preparations may preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with the blood.
  • Injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound.
  • Suitable pharmaceutical compositions for rectal administration are preferably as single dose suppositories. These can be prepared by mixing a compound according to formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
  • Suitable pharmaceutical compositions for topical application to the skin are preferably as an ointment, cream, lotion, paste, spray, aerosol or oil.
  • Vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances can be used as the carrier.
  • the active ingredient is generally present at a level of from 0.1% to 15% by weight of the composition, for example from 0.5% to 2%.
  • Suitable pharmaceutical compositions for transdermal applications may exist as single patches suitable for long-term close contact with the epidermis of the patient. Such patches suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer.
  • a suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%.
  • the active ingredient can be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
  • active ingredients for the combination preparations are suitable: All antidiabetic medicines mentioned in the Red List 2006, chapter 12; all weight loss / appetite suppressants listed in the Red List 2006, Chapter 1; all lipid-lowering drugs mentioned in the Red List 2006, chapter 58. They can be combined with the compound of the formula I according to the invention in particular for the synergistic effect improvement.
  • the administration of the active ingredient combination can be carried out either by separate administration of the active ingredients to the patient or in the form of combination preparations in which several active ingredients are present in a pharmaceutical preparation. Most of the drugs listed below are disclosed in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
  • Antidiabetic agents include insulin and insulin derivatives, e.g. Lantus® (see www.lantus.com) or HMR 1964 or Levemir® (insulin detemir) or those as described in WO2005005477 (Novo Nordisk), fast-acting insulins (see US 6,221,633), inhalable insulins such. Exubera® or oral insulins, such as. For example, IN-105 (Nobex) or Oral-lyn TM (Generex Biotechnology), GLP-I derivatives such as e.g.
  • the orally active hypoglycans are preferably sulfonylureas
  • GLP-1 agonists e.g. those described in WO 97/26265 and WO
  • PTPlB protein tyrosine phosphatase-1B
  • Modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2), fat metabolism-altering compounds such as antihyperlipidemic agents and antilipidemic agents, compounds that reduce food intake,
  • the compounds of the formula I are administered in combination with a TR- ⁇ agonist (thyroid receptor).
  • the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor (hydroxymethylglutaryl-coenzymes A) such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, L-659699.
  • HMGCoA reductase inhibitor hydroxymethylglutaryl-coenzymes A
  • the compound of formula I is used in combination with a cholesterol absorption inhibitor such as ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol / campesterol ascorbyl phosphate; Forbes Medi-Tech, WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497, WO2005021495) or with Compounds as described in WO2002066464 (Kotobuki Pharmaceutical Co.
  • a cholesterol absorption inhibitor such as ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol / campesterol ascorbyl phosphate; Forbes Medi-Tech, WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497, WO2005021495) or with Compounds as described in WO2002066464 (Kotobuki Pharmaceutical Co.
  • the compound of formula I is administered in combination with Vytorin TM, a fixed combination of ezetimibe with simvastatin. In one embodiment of the invention, the compound of formula I is administered in combination with a fixed combination of ezetimibe with fenofibrate.
  • the compound of formula I is administered in combination with a fixed combination of fenofibrate with rosuvastatin.
  • the compound of formula I is administered in combination with ISIS-301012, an antisense oligonucleotide capable of regulating the apolipoprotein B gene.
  • the compound of formula I is used in combination with a PPAR gamma agonist (peroxisome proliferator-activated receptors), such as e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570, R-483, CS-Ol 1 (rivoglitazone).
  • a PPAR gamma agonist peroxisome proliferator-activated receptors
  • the compound of formula I is administered in combination with Competact TM, a solid combination of pioglitazone hydrochloride with metformin hydrochloride.
  • the compound of formula I is administered in combination with duetact TM, a solid combination of pioglitazone hydrochloride with glimepiride.
  • the compound of formula I is administered in combination with Avandamet®, a solid combination of rosiglitazone maleate with metformin hydrochloride.
  • the compound of the formula I is administered in combination with PPAR alpha agonists, such as eg GW9578, GW-590735, K-11, LY-674, KRP-101, DRF-10945.
  • the compound of formula I is used in combination with a mixed PPAR alpha / gamma agonist, e.g. Naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, or as described in PCT / US 00/11833, PCT / US 00/11490, DE10142734.4 or in JP Berger et al., TRENDS in Pharmacological Sciences 28 (5), 244-251, 2005.
  • a mixed PPAR alpha / gamma agonist e.g. Naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, or as described in PCT / US 00/11833, PCT / US 00/11490, DE10142734.4 or in JP Berger et al., TRENDS in Pharmacological Sciences 28 (5), 244-251, 2005.
  • the compound of formula I is used in combination with a PPAR delta agonist, e.g. GW-501516 administered.
  • a PPAR delta agonist e.g. GW-501516 administered.
  • the compound of formula I is administered in combination with metaglidases or with MBX-2044 or other partial PPAR gamma agonist / antagonist
  • AMPK AMP-activated protein kinase
  • the compound of formula I is used in combination with a fibrate, e.g. Fenofibrate, clofibrate, bezafibrate.
  • a fibrate e.g. Fenofibrate, clofibrate, bezafibrate.
  • the compound of formula I is used in combination with an MTP inhibitor (microsomal triglyceride transfer protein), e.g. Implitapide, BMS-201038, R-103757 or those as described in WO2005085226, WO2005121091, WO2006010423.
  • MTP inhibitor microsomal triglyceride transfer protein
  • the compound of the formula I is administered in combination with a 5HT agonist (serotonin reuptake).
  • the compound of formula I is in combination with a CETP inhibitor (cholesterol ester transfer protein), such as torcetrapib or JTT-705 or those as described in WO2006002342, WO2006010422, WO2006012093.
  • a CETP inhibitor cholesterol ester transfer protein
  • the compound of formula I is used in combination with bile acid resorption inhibitor (see, e.g., U.S. 6,245,744, U.S. 6,221,897 or U.S. Pat
  • WO00 / 615678 e.g. HMR 1741 or as described in DE 10 2005 033099.1 and DE 10 2005 033100.9.
  • the compound of formula I is used in combination with a polymeric bile acid adsorber, such as e.g. Cholestyramine, colesevelam.
  • a polymeric bile acid adsorber such as e.g. Cholestyramine, colesevelam.
  • the compound of the formula I in combination with an LDL receptor inducers (low-density lipoprotein - see US 6,342,512), such. HMRI 171, HMRI 586, or those as described in WO2005097738.
  • the compound of the formula I is administered in combination with Omacor® (omega-3 fatty acids, highly concentrated ethyl esters of eicosapentaenoic acid and docosahexaenoic acid).
  • Omacor® omega-3 fatty acids, highly concentrated ethyl esters of eicosapentaenoic acid and docosahexaenoic acid.
  • the compound of the formula I is administered in combination with an ACAT inhibitor (acyl-CoA: cholesterol acyltransferase), e.g. Avasimibe or SMP-797.
  • ACAT inhibitor acyl-CoA: cholesterol acyltransferase
  • the compound of formula I is used in combination with an antioxidant, e.g. OPC-14117, probucol, tocopherol, ascorbic acid, beta-carotene or selenium.
  • an antioxidant e.g. OPC-14117, probucol, tocopherol, ascorbic acid, beta-carotene or selenium.
  • the compound of the formula I in combination with a vitamin, such as. As vitamin B6 or vitamin B12 administered.
  • the compound of formula I is administered in combination with a lipoprotein-lipase modulator, such as ibrolipim (NO-1886).
  • a lipoprotein-lipase modulator such as ibrolipim (NO-1886).
  • the compound of formula I is administered in combination with an ATP citrate lyase inhibitor (adenosine triphosphate citrate lyase) such as SB-204990.
  • the compound of the formula I is administered in combination with a TNF agonists (tumor necrosis factor).
  • the compound of formula I is used in combination with a squalene synthetase inhibitor, e.g. BMS-188494 or as described in WO2005077907.
  • a squalene synthetase inhibitor e.g. BMS-188494 or as described in WO2005077907.
  • the compound of formula I in combination with a lipoprotein (a) antagonist such as e.g. Gemcabene (CI-1027).
  • the compound of formula I is administered in combination with an agonist of GPR10A (HM74A receptor agonist), e.g. Nicotinic acid or "extended release niacin" in conjunction with MK-0524A or such compounds as described in WO2006045565, WO2006045564, WO2006069242 administered.
  • GPR10A HM74A receptor agonist
  • the compound of formula I is used in combination with an agonist of GPR16, as described e.g. in WO2006067531, WO2006067532.
  • the compound of formula I is administered in combination with a lipase inhibitor, e.g. Orlistat or cetilistat (ATL-962).
  • a lipase inhibitor e.g. Orlistat or cetilistat (ATL-962).
  • the compound of the formula I is administered in combination with insulin.
  • the compound of formula I is administered in combination with a sulfonylurea such as tolbutamide, glibenclamide, glipizide or glimepiride.
  • a sulfonylurea such as tolbutamide, glibenclamide, glipizide or glimepiride.
  • the compound of the formula I in combination with an insulin secretion-enhancing substance, such as. KCP-265 (WO2003097064).
  • the compound of the formula I in combination with agonists of the glucose-dependent insulinotropic receptor (GDIR) such.
  • GDIR glucose-dependent insulinotropic receptor
  • the compound of formula I is used in combination with a biguanide, e.g. Metformin, administered.
  • a biguanide e.g. Metformin
  • the compound of formula I is used in combination with a thiazolidinedione, e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, particularly 5 - [[4- [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione.
  • a thiazolidinedione e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, particularly 5 - [[4- [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl]
  • the compound of formula I is administered in combination with an ⁇ -glucosidase inhibitor, e.g. Miglitol or acarbose, administered.
  • an ⁇ -glucosidase inhibitor e.g. Miglitol or acarbose
  • the compound of formula I is administered in combination with an agent which acts on the ATP-dependent potassium channel of beta cells, e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • an agent which acts on the ATP-dependent potassium channel of beta cells e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • the compound of formula I is used in combination with more than one of the aforementioned compounds, e.g. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
  • the compound of the formula I is used in combination with an inhibitor of glycogen phosphorylase, such as PSN-357 or FR-258900 or such in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932.
  • an inhibitor of glycogen phosphorylase such as PSN-357 or FR-258900 or such in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932.
  • the compound of formula I is used in combination with glucagon receptor antagonists, such as e.g. A-770077 or NNC-25-2504 or as described in WO2004100875, WO2005065680.
  • glucagon receptor antagonists such as e.g. A-770077 or NNC-25-2504 or as described in WO2004100875, WO2005065680.
  • the compound of the formula I in combination with activators of glucokinase such as. LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50, or those as described e.g. As described in WO2004072031, WO2004072066, WO2005080360, WO2005044801, WO2006016194, WO2006058923.
  • the compound of the formula I in combination with an inhibitor of gluconeogenesis, such as. FR-225654.
  • the compound of the formula I is used in combination with inhibitors of fructose-l, 6-bisphosphatase (FBPase), e.g. CS-917 (MB-06322) or MB-07803 or those as described in WO2006023515.
  • FBPase 6-bisphosphatase
  • the compound of the formula I in combination with modulators of the glucose transporter-4 (GLUT4), such as. KST-48 (D.O. Lee et al .: Arzneim.-Forsch.drug Res. 54 (12), 835 (2004)).
  • the compound of the formula I in combination with inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), as z. As described in WO2004101528 administered.
  • GFAT glutamine-fructose-6-phosphate amidotransferase
  • the compound of formula I is administered in combination with Januvia TM, a solid combination of sitagliptin phosphate with metformin hydrochloride.
  • the compound of formula I in combination with inhibitors of 11-beta-hydroxysteroid dehydrogenase-l such.
  • l lß-HSDl 11-beta-hydroxysteroid dehydrogenase-l
  • the compound of formula I in combination with inhibitors of protein tyrosine phosphatase-1B (PTPlB), as described, for. In WO2001 19830-31,
  • the compound of the formula I is used in combination with modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2), such as KGA-2727, T-1095, SGL-0010, AVE 2268 and SAR 7226 or as described e.g. , In WO2004007517, WO200452903, WO200452902, PCT / EP2005 / 005959, WO2005085237, JP2004359630, WO2005121161, WO2006018150, WO2006035796, WO2006062224, WO2006058597 or AL Handion in Expert Opin. Ther. Patents (2005) 15 (11), 1531-1540.
  • the compound of formula I is administered in combination with modulators of GPR40.
  • the compound of the formula I in combination with modulators of GPRl 19b, as described, for. As described in WO2004041274 administered.
  • the compound of the formula I is used in combination with modulators of the GPRI 19, as described, for. As described in WO2005061489 (PSN-632408) administered. In one embodiment, the compound of the formula I in combination with inhibitors of hormone-sensitive lipase (HSL), such. As described in WO2005073199 administered.
  • HSL hormone-sensitive lipase
  • the compound of the formula I in combination with inhibitors of acetyl-CoA carboxylase (ACC) such as those described in WO199946262, WO200372197, WO2003072197, WO2005044814, WO2005108370, JP2006131559.
  • ACC acetyl-CoA carboxylase
  • the compound of formula I is used in combination with an inhibitor of phosphoenolpyruvate carboxykinase (PEPCK), e.g. such as described in WO2004074288 administered.
  • PPCK phosphoenolpyruvate carboxykinase
  • the compound of formula I in combination with an inhibitor of protein kinase C beta such as. B. Ruboxistaurin administered.
  • PLC beta protein kinase C beta
  • the compound of formula I in combination with an endothelin A receptor antagonist, such as. B. avosentan (SPP-301).
  • the compound of the formula I is administered in combination with inhibitors of the "I-kappaB kinase" (IKK inhibitors), as described, for example, in WO2001000610, WO2001030774, WO2004022553, WO2005097129.
  • the compound of the formula I in combination with modulators of the glucocorticoid receptor, as described, for. As described in WO2005090336 administered.
  • NPY antagonists neuropeptide Y
  • NPY-5 receptor antagonists such as L-152804, S-2367 or as such.
  • Peptide YY 3-36 PYY3-36 or analogous compounds such.
  • CJC-1682 PYY3-36 conjugated to human serum albumin via Cys34
  • CJC-1643 derivative of PYY3-36 conjugated to serum albumin in vivo
  • CBIR cannabinoid receptor 1 antagonists
  • rimonabant such as rimonabant, SR147778, SLV-319, AVE-1625, MK-0364 or salts thereof or such compounds as described in, for example, EP 0656354, WO 00/15609, WO 02/076949 , WO2005080345, WO2005080328, WO2005080343, WO2005075450, WO2005080357, WO200170700, WO2003026647-48, WO200302776, WO2003040107, WO2003007887, WO2003027069, US6,509,367, WO200132663,
  • Cannabinoid receptor 1 / cannabinoid receptor 2 (CB1 / CB2) modulating compounds as described e.g. in WO2007001939, WO2007044215, WO2007047737 are described;
  • MC4 agonists (melanocortin-4 receptor agonists eg 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo-2,3] 3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-chloro-phenyl) -2-oxo-ethyl] -amide; (WO 01/91752) ) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141 or those as described in WO2005060985, WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720, US20050124652, WO2005051391, WO2004112793, WO200200222214, US200501767
  • CRF antagonists corticotropin releasing factor antagonists, eg [2-methyl-9- (2,4,6-trimethylphenyl) -9H-l, 3,9-triaza-fluoren-4-yl] -dipropyl- amine (WO 00/66585)); CRF BP antagonists (eg, urocortin); Urocortin agonists; Agonists of the beta-3 adrenoceptor such as 1- (4-chloro-3-methanesulfonylmethyl-phenyl) -2- [2- (2,3-dimethyl-1H-indol-6-yloxy) -ethyl-amino] -ethanol hydrochloride (WO 01/83451) or Solabegron (GW-427353) or N-5984 (KRP-204) or those as described in JP20061 1 1553;
  • MSH melanocyte-stimulating hormone
  • MCH (melanin-concentrating hormone) receptor antagonists such as NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71, GW-803430 or such compounds, as described in WO2003 / 15769, WO2005085200, WO2005019240, WO2004011438, WO2004012648,
  • CCK-A agonists Cyclic pseudopeptide cholecystokinin A agonists such as ⁇ 2- [4- (4-
  • Serotonin reuptake inhibitors e.g., dexfenfluramines
  • mixed sertonine and noradrenergic compounds e.g., WO 00/71549
  • 5-HT receptor agonists e.g. 1- (3-ethyl-benzofuran-7-yl) -piperazine oxalic acid salt (WO
  • 5-HT2C receptor agonists such as Lorcaserin hydrochloride (APD-356) or BVT-933 or those as described in WO200077010, WO20077001-02, WO2005019180, WO2003064423,
  • 5-HT6 receptor antagonists as e.g. in WO2005058858 are described;
  • BRS-3 agonists Bombesin receptor agonists
  • Galanin receptor antagonists e.g., human growth hormone or AOD-9604;
  • Ghrelin antagonists such as B.
  • TRH agonists thyrotrophin-releasing hormones - see eg EP 0 462 884
  • decoupling protein 2 or 3 modulators Leptin agonists (see, eg, Lee, Daniel W, Leinung, Matthew C, Rozhavskaya Arena, Marina, Grasso, Patricia, Leptin agonists as a Potential Approach to the Treatment of Obesity, Drugs of the Future (2001), 26 (9), 873-881);
  • DA agonists dopamine agonist, eg bromocriptine, doprexine
  • Lipase / amylase inhibitors eg WO 00/40569
  • Inhibitors of diacylglycerol O-acyltransferases such. B. BAY-74-4113 or such.
  • DGATs diacylglycerol O-acyltransferases
  • FES fatty acid synthase
  • thyroid hormone receptor agonists such as. B: KB-2115 or those as described in WO20058279, WO200172692, WO200194293, WO2003084915, WO2004018421, WO2005092316.
  • the other active ingredient is varenicline tartrate, a partial agonist of the alpha 4-beta 2 nicotinic acetylcholine receptor.
  • the other active ingredient is trodusquemine.
  • the further active ingredient is a modulator of the enzyme SIRT1, a member of the human sirtuin enzyme family.
  • the further active ingredient is leptin; see, e.g. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622.
  • the other active ingredient is dexamphetamine or amphetamine. In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine.
  • the other active ingredient is sibutramine.
  • the other active ingredient is mazindol or phentermine.
  • the further active ingredient is a diphenylazetidinone derivative, e.g. in US 6,992,067 or US 7,205,290.
  • the compound of formula I is used in combination with dietary fiber, preferably insoluble fiber (see, e.g., Carob / Caromax® (Zunft HJ; et al., Carob pulp preparation for the treatment of hypercholesterolemia, ADVANCES IN
  • Caromax is a carob-containing product from the company Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark availability, 65926 Frankfurt / Main)) administered.
  • the combination with Caromax® can be carried out in one preparation or by separate administration of compounds of the formula I and Caromax®.
  • Caromax® can also be used in the form of foods, such as in baked goods or muesli bars.
  • Human glucokinase is expressed as a fusion protein with glutathione S-transferase (GST) in E. coli B121 and purified by affinity chromatography. By digesting with factor Xa, GSH is cleaved off and the glucokinase polypeptide is obtained beginning with Ser-6. The latter is purified by chromatography. A typical preparation of glucokinase has a specific activity of 30 U / mg protein at room temperature.
  • GST glutathione S-transferase
  • the activity of glucokinase and the effect of compounds on this activity are determined by a coupled optical assay at 25 ° C.
  • the test volume is 100 ⁇ l.
  • the test composition is: 25mM HEPES / NaOH (Merck, # 110110) pH 7, 25mM KCl (Merck; # 04933), 2mM MgCl 2 (Merck; # 05833), 1mM Dithiothreitol (Merck; # 112013), 1 mM NAD (Sigma; # N151 1), 5mM glucose (Merck; # 108337), 1mM ATP (Sigma; # A2383), 0.1% (w / v) bovine serum albumin (Merck; # 112018), 0.002 U glucokinase -
  • test compound Preparation and 3.2 U glucose-6-phosphate dehydrogenase (Sigma; # G8529). Furthermore, the approach contains a test compound.
  • the test compounds are each dissolved in 10 mM DMSO and are tested at final concentrations of 0 ⁇ M, 0.1 ⁇ M, 0.3 ⁇ M, 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, 30 ⁇ M and 100 ⁇ M.
  • the final concentration of DMSO in the test is 1% (v / v).
  • the reaction is started by the addition of ATP.
  • the absorption of the batch at 340 nm is determined immediately after the addition of ATP and then 25 minutes later with a multiwell plate photometer (Labsystems, Multiskan Ascent). The change in absorbance over this period is calculated.
  • the raw data of the extinction changes are transferred to a Microsoft Excel file.
  • the value for 0 ⁇ M test compound is set as 100%.
  • Dose-response curves are calculated using the XL program. Fit calculated according to the manufacturer's specifications (IDBS company).
  • IDBS company manufacturer's specifications
  • the compounds according to the invention cause activation of glucokinase. These compounds are thus particularly suitable for lowering the blood sugar level and for the treatment of diabetes.
  • a phenothiazine ester (R methyl or ethyl) of the general formula A-1 (preparation described in DE2007-002), wherein R 1, R 2 and R 3 have the abovementioned meanings, is reacted in a polar aprotic solvent such as, for example, acetonitrile with a base such as For example, l, 8-diazabicyclo [5.4.0] undec-7-ene deprotonated at room temperature and then treated at low temperature (-20 ° C - 0 ° C) with 4-Acetaminobenzolsulfonylazid and then allowed to react at room temperature.
  • a polar aprotic solvent such as, for example, acetonitrile
  • a base such as For example, l, 8-diazabicyclo [5.4.0] undec-7-ene deprotonated at room temperature and then treated at low temperature (-20 ° C - 0 ° C) with 4-Aceta
  • the resulting diazo compound is not isolated but reacted by addition of an oxidizing agent such as oxone in a solvent mixture such as acetone / toluene in the presence of a base, such as sodium bicarbonate, to the keto compound of general formula A-2.
  • the keto compound of general formula A-2 is reacted with a Wittig reagent which is obtained by liberation of the corresponding Wittigsalzes of general formula A-3 by a base such as lithium hexamethyldisilazide in a polar aprotic solvent like
  • Coupling reagents such as O- [cyano (ethoxycarbonyl) methyleneamino] -1, 1,3,3-tetramethyluronium tetrafluoroborate (TOTU) or [dimethylamino - [[1,2,3] triazolo [4,5-b] pyridine 3-yloxy) -methylene] -dimethyl-ammonium hexafluoro-phosphate (HATU) / [1,2,3] triazolo [4,5-b] pyridin-3-ol (HOAT) in the presence of a base such as diisopropylethylamine in a polar aprotic solvent such as N, N-dimethylformamide, the carboxylic acid of general formula A-5 with the amine of general formula A-6, wherein A, R4 and R5 have the meanings described above, to the amide of general formula A-7 implemented.
  • the racemic compounds of general formula A-7 can be separated into the enantiomers by
  • Examples 1-5 were prepared by Method A.
  • this solution is added dropwise to a stirred suspension 2.53 g of cyclopentylmethyl triphenyl phosphonium iodide in 60 ml of tetrahydrofuran with ice cooling.
  • the reaction mixture is stirred for 45 minutes at 0 ° C., then 1.85 g (10-methyl-5,5-dioxo-5,10-dihydro-2-phenothiazin-2-yl) -oxoacetate dissolved in 20 ml of THF are added dropwise and a Stirred at 0 ° C for 1 hour.
  • the cooling bath is removed and allowed to warm slowly to room temperature.
  • the reaction mixture is stirred overnight at room temperature.
  • Diisopropylethylamine are dissolved in 10 ml of dimethylformamide. Add 318 mg HATU and 1 14 mg HOAT and stir at room temperature for 2 hours. Thereafter, the reaction mixture is diluted by adding 100 ml of ethyl acetate and washed five times with 30 ml of water. The organic phase is dried over MgSO 4 and then the solvent is removed in vacuo. The residue is chromatographed on silica gel with the eluent n-

Abstract

L'invention concerne des composés de formule (I) dans laquelle les restes R1, R2, R3, R4, R5, R6 et R7, ainsi que A et B ont les significations mentionnées. L'invention concerne également leurs sels physiologiquement compatibles. Ces composés s'utilisent par ex. comme antidiabétiques.
PCT/EP2008/007219 2007-09-21 2008-09-04 Dérivés de phénothiazine à liaison double, procédé pour les produire et leur utilisation comme médicaments WO2009039944A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP08785816A EP2203448B1 (fr) 2007-09-21 2008-09-04 Dérivés de phénothiazine à liaison double, procédé pour les produire et leur utilisation comme médicaments
AT08785816T ATE513830T1 (de) 2007-09-21 2008-09-04 Phenothiazin-derivate mit doppelbindung, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
US12/724,520 US8207146B2 (en) 2007-09-21 2010-03-16 Phenothiazine derivative having a double bond, method for the production thereof, and use thereof as a pharmaceutical

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP07291133.2 2007-09-21
EP07291133 2007-09-21

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/724,520 Continuation US8207146B2 (en) 2007-09-21 2010-03-16 Phenothiazine derivative having a double bond, method for the production thereof, and use thereof as a pharmaceutical

Publications (1)

Publication Number Publication Date
WO2009039944A1 true WO2009039944A1 (fr) 2009-04-02

Family

ID=39144335

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2008/007219 WO2009039944A1 (fr) 2007-09-21 2008-09-04 Dérivés de phénothiazine à liaison double, procédé pour les produire et leur utilisation comme médicaments

Country Status (4)

Country Link
US (1) US8207146B2 (fr)
EP (1) EP2203448B1 (fr)
AT (1) ATE513830T1 (fr)
WO (1) WO2009039944A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012030165A2 (fr) 2010-08-31 2012-03-08 서울대학교산학협력단 Utilisation de la reprogrammation fœtale d'un agoniste des ppar δ
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
CN106749098A (zh) * 2016-12-07 2017-05-31 大连万福制药有限公司 一种以氧气为氧化剂制备盐酸二氧丙嗪的绿色工艺

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001044216A1 (fr) * 1999-12-15 2001-06-21 F. Hoffmann-La Roche Ag Activateurs transolefiniques de glucokinase
WO2002062772A1 (fr) * 2001-02-05 2002-08-15 Dr. Reddy's Research Foundation Derives de sels d'acide 3-4(4-(2-phenoxazin- ou phenothiazin-10-yl)alkoxy)phenyl)-2-alcoxypropanoique a activite ppar pour le traitement de l'hyperlipemie et du diabete de type ii
WO2005095417A1 (fr) * 2004-04-02 2005-10-13 Novartis Ag Derives thiazolopyridine, compositions pharmaceutiques les contenant et procedes de traitement de troubles a mediation par glucokinase

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999038501A2 (fr) * 1998-02-02 1999-08-05 Trustees Of Tufts College Procede de regulation du metabolisme du glucose et reactifs afferents
PE20011074A1 (es) * 2000-02-23 2001-10-04 Upjohn Co Uso de pramipexol en el tratamiento de trastornos de adiccion
US6608038B2 (en) * 2000-03-15 2003-08-19 Novartis Ag Methods and compositions for treatment of diabetes and related conditions via gene therapy
US6897231B2 (en) * 2000-07-31 2005-05-24 Signal Pharmaceuticals, Inc. Indazole derivatives as JNK inhibitors and compositions and methods related thereto
ITRM20020016A1 (it) * 2002-01-15 2003-07-15 Sigma Tau Ind Farmaceuti Derivati di acidi fenil(alchil)carbossilici e derivati fenilalchileterociclici dionici, loro uso come medicamenti ad attivita' ipoglicemizza

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001044216A1 (fr) * 1999-12-15 2001-06-21 F. Hoffmann-La Roche Ag Activateurs transolefiniques de glucokinase
WO2002062772A1 (fr) * 2001-02-05 2002-08-15 Dr. Reddy's Research Foundation Derives de sels d'acide 3-4(4-(2-phenoxazin- ou phenothiazin-10-yl)alkoxy)phenyl)-2-alcoxypropanoique a activite ppar pour le traitement de l'hyperlipemie et du diabete de type ii
WO2005095417A1 (fr) * 2004-04-02 2005-10-13 Novartis Ag Derives thiazolopyridine, compositions pharmaceutiques les contenant et procedes de traitement de troubles a mediation par glucokinase

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012030165A2 (fr) 2010-08-31 2012-03-08 서울대학교산학협력단 Utilisation de la reprogrammation fœtale d'un agoniste des ppar δ
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
CN106749098A (zh) * 2016-12-07 2017-05-31 大连万福制药有限公司 一种以氧气为氧化剂制备盐酸二氧丙嗪的绿色工艺

Also Published As

Publication number Publication date
US20100261643A1 (en) 2010-10-14
EP2203448A1 (fr) 2010-07-07
US8207146B2 (en) 2012-06-26
ATE513830T1 (de) 2011-07-15
EP2203448B1 (fr) 2011-06-22

Similar Documents

Publication Publication Date Title
EP2084172B1 (fr) Nouveaux dérivés de 1,4-benzothiépine-1,1-dioxyde substitués par des restes benzyle, procédé de production approprié, médicaments contenant lesdits composés et leur utilisation
EP2083832B1 (fr) Nouveaux dérivés de 1,4-benzothiépine-1,1-dioxyde aux propriétés améliorées, procédé de production approprié, médicaments contenant lesdits composés et leur utilisation
DE102006053637B4 (de) Neue mit Fluor substituierte 1,4-Benzothiepin-1,1-Dioxidderivate, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
EP2114937B1 (fr) Dérivé de phénothiazine, procédé pour sa fabrication et utilisation de celui-ci en tant que médicament
EP2084143B1 (fr) Nouveaux dérivés de 1,4-benzothiépine-1,1-dioxyde substitués par des restes cyclohexyle, procédé de production approprié, médicaments contenant lesdits composés et leur utilisation
EP1940807B1 (fr) Derives de carbamoyle-benzotriazol utilises comme inhibiteurs de lipases et de phospholipases
EP2144885B1 (fr) Dérivés d'amide d'acide imidazolidine-carboxylique utilisés comme inhibiteurs de lipases et de phospholipases
WO2009039943A1 (fr) (carboxyalkylène-phényl)-phényl-oxalamides, procédé pour leur fabrication et leur utilisation comme médicaments
EP2203415A1 (fr) (cyclopropyl-phenyl)-phenyl-oxalamides, procede pour leur fabrication et leur utilisation comme medicaments
EP2203448B1 (fr) Dérivés de phénothiazine à liaison double, procédé pour les produire et leur utilisation comme médicaments
EP2144891B1 (fr) 5-oxo-isoxazole en tant qu'inhibiteurs de lipases et phospholipases
EP2683702B1 (fr) Nouveaux dérivés de phényle-oxathiazine substitués, leur procédé de fabrication, médicament contenant ces liaisons et son utilisation
DE102007005045B4 (de) Phenothiazin Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
EP2683698B1 (fr) Dérivés benzyl-oxathiazine substitués avec adamantane ou noradamantane, médicaments contenant ces composés et leur utilisation
EP2683703B1 (fr) Nouveaux dérivés phényl-oxathiazine substitués, procédé pour leur préparation, agent pharmaceutique contenant ces composés et leur utilisation
EP2683701B1 (fr) Dérivés d'oxathiazine substitués par des groupes de benzyle-méthyles ou d'hétéro-méthyles, leur procédé de fabrication, leur utilisation comme médicament ainsi que médicaments en étant pourvu et leur utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08785816

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2008785816

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE